Parkinsonism characterizes the motor symptoms of Parkinson's disease and other related neurodegenerative conditions (e.g., multiple system atrophy, progressive supranuclear palsy and dementia with Lewy bodies) to varied degrees. Parkinsonism includes resting tremor, rigidity, postural abnormalities, gait disturbances and bradykinesia/akinesia. Although traditional accounts emphasize the role of reduced dopamine (DA) transmission in the basal ganglia (secondary to loss of midbrain A9 dopamine neurons) in the motoric defects of these disorders, more recent data support the concept that degeneration of brainstem circuitry beyond the midbrain DA group may be important contributors to the development of parkinsonism and therefore present a potential therapeutic target. The objective of the present proposal is to delineate the role of the mesencephalic locomotor region (MLR), a pontine structure linking basal ganglia output with spinal cord motor circuitry, in the pathophysiology of Parkinsonism. To accomplish this objective, we have designed three specific aims that combine neuroanatomical, neurochemical and neurogenetic approaches to delineate the roles of the MLR and two adjacent areas of the lateral pontine tegmentum, the pedunculopontine tegmental nucleus (PPT) and the midbrain extrapyramidal area (MEA), in motor control. Based upon our preliminary data, we hypothesize two major pathways linking key basal ganglia output nuclei with spinal cord motor circuitry: (1) an extensor circuit regulating postural tone by extensor muscles in the limbs and (2) a flexor circuit, necessary for locomotion and to perform specific tasks. The extensor circuit utilizes a presumably dopaminergic input from the substantia nigra pars compacta (SNc) to the ventral MLR while the extensor circuit is comprised of a presumably GABAergic projection from the substantia nigra pars reticulata (SNr) to the glutamatergic MEA, and from there to neurons in the dorsal MLR. Both the extensor and flexor circuits are then served by glutamatergic neurons that directly innervate the spinal cord. By elucidating the neuroanatomic connections and neurochemical mechanisms by which the mesencephalic locomotor region relays basal ganglia output to spinal motor cord circuitry, therapeutic and diagnostic strategies may be developed for individuals suffering from Parkinsonism and possibly other movement disorders such as cataplexy. PUBLIC HEALTH RELEVANCE The motor symptoms of Parkinson's disease and other related neurodegenerative conditions (e.g., synucleinopathies) are characterized by variable degrees of parkinsonism, which includes resting tremor, rigidity, postural abnormalities, gait disturbances and bradykinesia/akinesia. The objective of the present proposal is to delineate the role of the mesencephalic locomotor region (MLR), a pontine structure linking basal ganglia output with spinal cord motor circuitry, in the pathophysiology of Parkinsonism. Results from our studies will provide data important for the development of therapeutic and diagnostic strategies for treating Parkinsonism and possibly other movement disorders such as cataplexy.